CN111434665B - 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 - Google Patents

内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 Download PDF

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Publication number: CN111434665B
Authority: CN; China
Prior art keywords: compound; group; substituted; unsubstituted; alkyl
Prior art date: 2019-01-11
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

CN201910027573.6A

Other languages

English (en)

Chinese (zh)

Other versions

CN111434665A (zh

Inventor

王喆

曾志宏

张磊

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Shanghai Longwood Biopharmaceuticals Co Ltd

Original Assignee

Shanghai Longwood Biopharmaceuticals Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2019-01-11

Filing date

2019-01-11

Publication date

2023-03-10

2019-01-11 Priority to CN201910027573.6A priority Critical patent/CN111434665B/zh

2019-01-11 Application filed by Shanghai Longwood Biopharmaceuticals Co Ltd filed Critical Shanghai Longwood Biopharmaceuticals Co Ltd

2020-01-10 Priority to MX2021008386A priority patent/MX2021008386A/es

2020-01-10 Priority to SG11202107643YA priority patent/SG11202107643YA/en

2020-01-10 Priority to PH1/2021/551849A priority patent/PH12021551849A1/en

2020-01-10 Priority to AU2020205923A priority patent/AU2020205923B2/en

2020-01-10 Priority to CA3126570A priority patent/CA3126570A1/en

2020-01-10 Priority to JP2021540294A priority patent/JP7603320B2/ja

2020-01-10 Priority to KR1020217025454A priority patent/KR102650441B1/ko

2020-01-10 Priority to EP20738690.5A priority patent/EP3909957A4/de

2020-01-10 Priority to CN202080008964.4A priority patent/CN113286798B/zh

2020-01-10 Priority to US17/421,819 priority patent/US20220380384A1/en

2020-01-10 Priority to PCT/CN2020/071523 priority patent/WO2020143798A1/zh

2020-01-10 Priority to BR112021013730-0A priority patent/BR112021013730A2/pt

2020-07-21 Publication of CN111434665A publication Critical patent/CN111434665A/zh

2021-07-30 Priority to ZA2021/05438A priority patent/ZA202105438B/en

2023-03-10 Application granted granted Critical

2023-03-10 Publication of CN111434665B publication Critical patent/CN111434665B/zh

Status Active legal-status Critical Current

2039-01-11 Anticipated expiration legal-status Critical

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 187
208000002672 hepatitis B Diseases 0.000 title claims abstract description 18
150000003839 salts Chemical class 0.000 claims abstract description 28
239000012453 solvate Substances 0.000 claims abstract description 16
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
239000003112 inhibitor Substances 0.000 claims abstract description 6
230000010076 replication Effects 0.000 claims abstract description 4
238000006243 chemical reaction Methods 0.000 claims description 59
125000000217 alkyl group Chemical group 0.000 claims description 24
241000700721 Hepatitis B virus Species 0.000 claims description 23
229910052736 halogen Inorganic materials 0.000 claims description 23
150000002367 halogens Chemical class 0.000 claims description 20
125000004093 cyano group Chemical group *C#N 0.000 claims description 14
229910052739 hydrogen Inorganic materials 0.000 claims description 14
238000000034 method Methods 0.000 claims description 14
125000001424 substituent group Chemical group 0.000 claims description 13
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
238000006467 substitution reaction Methods 0.000 claims description 8
125000004429 atom Chemical group 0.000 claims description 7
230000002401 inhibitory effect Effects 0.000 claims description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
239000001257 hydrogen Substances 0.000 claims description 6
239000002904 solvent Substances 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
125000005843 halogen group Chemical group 0.000 claims description 5
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
125000004450 alkenylene group Chemical group 0.000 claims description 4
125000002947 alkylene group Chemical group 0.000 claims description 4
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
238000000338 in vitro Methods 0.000 claims description 4
238000002360 preparation method Methods 0.000 claims description 4
229940127009 HBV antigen inhibitor Drugs 0.000 claims description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
239000012442 inert solvent Substances 0.000 claims description 2
229940079593 drug Drugs 0.000 claims 1
239000000126 substance Substances 0.000 abstract description 6
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 63
230000015572 biosynthetic process Effects 0.000 description 43
238000003786 synthesis reaction Methods 0.000 description 42
238000004440 column chromatography Methods 0.000 description 25
-1 monofluoromethyl Chemical group 0.000 description 23
229910052757 nitrogen Inorganic materials 0.000 description 21
229910052717 sulfur Inorganic materials 0.000 description 20
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
125000005842 heteroatom Chemical group 0.000 description 18
229910052760 oxygen Inorganic materials 0.000 description 17
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
230000000694 effects Effects 0.000 description 16
239000000047 product Substances 0.000 description 16
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
239000012043 crude product Substances 0.000 description 15
239000000243 solution Substances 0.000 description 14
239000000203 mixture Substances 0.000 description 13
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
239000012074 organic phase Substances 0.000 description 12
239000007787 solid Substances 0.000 description 12
238000004809 thin layer chromatography Methods 0.000 description 12
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KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
125000003545 alkoxy group Chemical group 0.000 description 10
125000000753 cycloalkyl group Chemical group 0.000 description 10
238000002474 experimental method Methods 0.000 description 10
125000000882 C2-C6 alkenyl group Chemical group 0.000 description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
238000005481 NMR spectroscopy Methods 0.000 description 9
125000003601 C2-C6 alkynyl group Chemical group 0.000 description 8
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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125000003118 aryl group Chemical group 0.000 description 8
235000018102 proteins Nutrition 0.000 description 8
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239000011780 sodium chloride Substances 0.000 description 8
125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 7
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JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
239000007995 HEPES buffer Substances 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
125000003282 alkyl amino group Chemical group 0.000 description 6
125000004432 carbon atom Chemical group C* 0.000 description 6
239000003921 oil Substances 0.000 description 6
235000019198 oils Nutrition 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
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239000003795 chemical substances by application Substances 0.000 description 5
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239000007850 fluorescent dye Substances 0.000 description 5
WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
238000003756 stirring Methods 0.000 description 5
238000012360 testing method Methods 0.000 description 5
125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 4
125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 description 4
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
HHTRAISBAAXRKZ-UHFFFAOYSA-N 5-amino-2-fluorobenzonitrile Chemical compound NC1=CC=C(F)C(C#N)=C1 HHTRAISBAAXRKZ-UHFFFAOYSA-N 0.000 description 4
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
125000000041 C6-C10 aryl group Chemical group 0.000 description 4
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CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
239000007864 aqueous solution Substances 0.000 description 4
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HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
239000002994 raw material Substances 0.000 description 4
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PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 3
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OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
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241000700605 Viruses Species 0.000 description 2
PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 2
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Virology (AREA)
Medicinal Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
Biotechnology (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Oncology (AREA)
Communicable Diseases (AREA)
Molecular Biology (AREA)
Engineering & Computer Science (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Hydrogenated Pyridines (AREA)

CN201910027573.6A 2019-01-11 2019-01-11 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 Active CN111434665B (zh)

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CN201910027573.6A CN111434665B (zh)	2019-01-11	2019-01-11	内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途
US17/421,819 US20220380384A1 (en)	2019-01-11	2020-01-10	Internal cyclic sulphiamidine amide-aryl amide compound and use thereof for treating hepatitis b
PH1/2021/551849A PH12021551849A1 (en)	2019-01-11	2020-01-10	Internal cyclic sulphiamidine amide-aryl amide compound and use thereof for treating hepatitis b
AU2020205923A AU2020205923B2 (en)	2019-01-11	2020-01-10	Internal cyclic sulphiamidine amide-aryl amide compound and use thereof for treating hepatitis B
CA3126570A CA3126570A1 (en)	2019-01-11	2020-01-10	Internal cyclic sulphiamidine amide-aryl amide compound and use thereof for treating hepatitis b
JP2021540294A JP7603320B2 (ja)	2019-01-11	2020-01-10	環内チアミジノアミド－アリールアミド系化合物及びｂ型肝炎を治療するためのその使用
KR1020217025454A KR102650441B1 (ko)	2019-01-11	2020-01-10	내부 사이클릭 설피아미딘 아미드-아릴 아미드 화합물 및 이의 b형 간염 치료를 위한 용도
EP20738690.5A EP3909957A4 (de)	2019-01-11	2020-01-10	Interne cyclische sulfiamidinamid-arylamid-verbindung und verwendung davon zur behandlung von hepatitis b
MX2021008386A MX2021008386A (es)	2019-01-11	2020-01-10	Compuesto interno de sulfiamidina amida-aril amida cíclica y su uso para el tratamiento de la hepatitis b.
SG11202107643YA SG11202107643YA (en)	2019-01-11	2020-01-10	Internal cyclic sulphiamidine amide-aryl amide compound and use thereof for treating hepatitis b
PCT/CN2020/071523 WO2020143798A1 (zh)	2019-01-11	2020-01-10	内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途
BR112021013730-0A BR112021013730A2 (pt)	2019-01-11	2020-01-10	Composto de sulfiamidina amida-arilamida cíclica interna e uso do mesmo para tratamento de hepatite b
CN202080008964.4A CN113286798B (zh)	2019-01-11	2020-01-10	内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途
ZA2021/05438A ZA202105438B (en)	2019-01-11	2021-07-30	Internal cyclic sulphiamidine amide-aryl amide compound and use thereof for treating hepatitis b

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CN202080008964.4A Active CN113286798B (zh)	2019-01-11	2020-01-10	内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途

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US (1)	US20220380384A1 (de)
EP (1)	EP3909957A4 (de)
JP (1)	JP7603320B2 (de)
KR (1)	KR102650441B1 (de)
CN (2)	CN111434665B (de)
AU (1)	AU2020205923B2 (de)
BR (1)	BR112021013730A2 (de)
CA (1)	CA3126570A1 (de)
MX (1)	MX2021008386A (de)
PH (1)	PH12021551849A1 (de)
SG (1)	SG11202107643YA (de)
WO (1)	WO2020143798A1 (de)
ZA (1)	ZA202105438B (de)

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CN115177624A (zh) *	2021-04-06	2022-10-14	上海长森药业有限公司	通过口服给药增加病毒空衣壳蛋白治疗hbv的方法

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WO2018153326A1 (zh) *	2017-02-22	2018-08-30	上海长森药业有限公司	磺酰肼类化合物及其用途
CN109251212A (zh) *	2017-07-14	2019-01-22	上海长森药业有限公司	内环硫醚酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途

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JP5977347B2 (ja)	2011-07-01	2016-08-24	バルークエス．ブルームバーグインスティテュート	Ｈｂｖ感染に対する抗ウイルス剤としてのスルファモイルベンズアミド誘導体
BR112014015197A8 (pt)	2011-12-21	2017-06-13	Novira Therapeutics Inc	agentes antivirais de hepatite b
TW201620893A (zh) *	2014-02-06	2016-06-16	健生科學愛爾蘭無限公司	磺醯胺基吡咯醯胺衍生物及其用作治療ｂ型肝炎之醫藥品的用途
WO2015155197A1 (en) *	2014-04-11	2015-10-15	Bayer Pharma Aktiengesellschaft	Novel macrocyclic compounds
US10875876B2 (en) *	2015-07-02	2020-12-29	Janssen Sciences Ireland Uc	Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
CN108250121A (zh) *	2016-12-28	2018-07-06	上海长森药业有限公司	磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途
CN108341810B (zh) *	2017-01-23	2022-01-18	上海长森药业有限公司	环硫脲类化合物及其用途
CN109251158B (zh) *	2017-07-14	2023-05-23	上海长森药业有限公司	硫脒酰胺类化合物及其用于乙型肝炎治疗的用途

2019
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2020
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- 2020-01-10 WO PCT/CN2020/071523 patent/WO2020143798A1/zh not_active Ceased
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WO2020143798A1 (zh)	2020-07-16
CN113286798A (zh)	2021-08-20
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AU2020205923B2 (en)	2022-12-01
CA3126570A1 (en)	2020-07-16
KR20210134621A (ko)	2021-11-10
CN111434665A (zh)	2020-07-21
US20220380384A1 (en)	2022-12-01
EP3909957A4 (de)	2022-09-07
EP3909957A1 (de)	2021-11-17
JP2022517984A (ja)	2022-03-11
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